In the physical rehabilitation setting, women typically demonstrate lesser return to function than men. Estrogen (E2) deficiency might contribute to the gender discrepancy, as low E2 levels have been linked to a decrease in lean muscle mass. Of the more than two million women receiving post-operative or rehabilitation care each year, approximately 1/2 of them are "estrogen-deficient" due to natural menopause, surgical menopause, and normal hormonal rhythms disrupted by illness or trauma. The overall goal of this translational research project is to use animal models to determine if exogenous E2 should be considered as an adjunct to standard physical rehabilitation for E2 deficient women. Prior studies in animals have demonstrated that a lack of circulating E2 (subsequent to ovariectomy (OVX)) impairs recovery of laboratory-induced atrophic skeletal muscle. Failure to regrow atrophied muscles in OVX rats was associated with failure to initiate protein synthesis. In contrast, E2 deficient rats with muscle atrophy that were given E2 hormone replacement therapy (HRT) demonstrated nearly complete regrowth of atrophied muscle within a week. Muscle regrowth with E2 HRT is associated with activation of the Akt/mTOR pathway of muscle protein synthesis. Moreover, E2 HRT restored myofiber cross-sectional area. The proposed project will elucidate mechanisms associated with the failure to regrow atrophied skeletal muscle in the E2 deficient female rat. We will conduct experiments that examine skeletal muscle regrowth for the E2-deficient rats receiving short-term E2 HRT and standard physical rehabilitation exercise. We will also examine the components of muscle regrowth (e.g., cross-sectional area). The specific aims are to: 1) determine the extent of atrophic skeletal muscle regrowth produced independently by E2 HRT or rehabilitation exercise in E2 deficient rats. 2) Determine if E2 HRT combined with rehabilitation exercise can augment the extent of atrophic skeletal muscle regrowth in E2 deficient rats. 3) Use estrogen receptor (ER) knock-out mice and ER-specific ligands to determine if the E2 effect on atrophic muscle regrowth is mediated through the ER1 or ER2 receptor. Concerns about the safety of E2 HRT compel investigation of an ER specific compound that will prove effective without undesirable side-effects. The proposed studies will lay the groundwork for determining the extent to which short-term estrogen (E2) therapy should be considered as an adjunct to standard physical rehabilitation care for estrogen deficient women. PUBLIC HEALTH RELEVANCE: Approximately 1/2 of the adult female population may be considered estrogen deficient due to menopause, surgery, trauma or illness. Estrogen deficiency has been linked to a decrease in lean muscle mass and impaired muscle regrowth following extended bed rest. Short-term estrogen hormone replacement therapy could provide a valuable addition to rehabilitation exercise protocols, but more information about the role and mechanism of estrogen effectiveness in skeletal muscle is needed.